This study determined the effects of hypoxia on diameter, vascular smooth muscle (VSM) transmembrane potential (E(m)), and vascular cAMP levels for in vitro cannulated skeletal muscle resistance arteries (gracilis arteries) from Sprague-Dawley rats fed a low-salt (LS) or a high-salt (HS) diet. Arterial diameter and VSM E(m) were measured in response to hypoxia, iloprost, cholera toxin, forskolin, and aprikalim. In HS rats, arterial dilation and VSM hyperpolarization after hypoxia, iloprost, and cholera toxin were impaired versus responses in LS rats, whereas responses to forskolin and aprikalim were unaltered. Blockade of prostaglandin H(2) and thromboxane A(2) receptors had no effect on responses to hypoxia or iloprost in vessels from both rat groups, suggesting that inappropriate activation of these receptors does not contribute to the impaired hypoxic dilation with HS. Hypoxia, cholera toxin, and iloprost increased vascular cAMP levels in vessels of LS rats only, whereas forskolin increased cAMP levels in all vessels. These data suggest that reduced hypoxic dilation of skeletal muscle microvessels in rats on a HS diet may reflect an impaired ability of VSM to produce cAMP after exposure to prostacyclin.